Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by arthritis, vasculitis, immune complex glomerulonephritis and infiltration of inflammation cells into the glomeruli. Pathogenesis of SLE is not fully understood although much progress has been made. Previous studies indicate that over expression of the Ets transcriptional factor Fli-1 is involved in disease development in murine models of lupus. Two to three-fold transgenic over expression of Fli-1 in normal mice results in the development of a lupus-like disease. Active lupus patients have higher Fli-1 mRNA in peripheral lymphocytes compared with normal controls. In preliminary studies for this proposal, we found that genetic reduction of Fli-1 expression in MRL/lpr mice significantly prolonged survival, decreased auto antibody production, and decreased renal pathologic proliferate changes. The protective effect of Fli-1 in murine lupus appears to be mediated through multiple factors including alterations in lymphocyte subsets and cytokine/chemokine production. The long-term objective of my research is to identify novel inflammation pathways in disease development in lupus, and eventually such new findings will enable development of novel therapeutics that target the specific inflammation pathway. The short-term objective of this K01 proposal is to define the mechanisms of reduced Fli-1 gene expression affecting disease development in MRL/lpr mouse, an animal model of SLE. Our hypothesis, based on our preliminary data, is that Fli-1 is a key pathogenic factor in lupus through its effects on B cell activation and the response of target organs to inflammatory stimuli. We will approach our short-term goals with the following specific aims proposed to address this hypothesis: Aim 1. Define the effects of Fli-1 on B cell activation, proliferation, differentiation and autoantibody production and resultant disease in MRL/lpr mice. Aim 2. Identify molecular mechanisms whereby Fli-1 affects the response of the kidney in MRUIpr mice to inflammatory stimuli. Aim 3. Determine effect of reduced expression of Fli-1 on disease development in NZM2410 mice.